Application Ser. No. 08/196,455 presents the background of multi-chambered syringes which are used for sequential injection and/or the mixing of drugs and solutions. Additional background of enclosed drug-mixing systems is provided in U.S. Pat. No. 4,614,267. As described within the backgrounds of the many patents presented in the aforementioned application, it is advantageous to store a drug in a powdered or liquid form and then mix the drug in the same enclosure which is subsequently placed in fluid connection with the patient. More specifically, it is advantageous to provide mixing within a syringe so that reconstitution within a separate drug vial becomes unnecessary. This, however, must be provided at minimum cost and would preferably utilize materials to store the drug, such as glass, which have been determined appropriate by the U.S. Food and Drug Administration for long-term storage of drugs so that the evaluation of the leaching or interaction between the drug and the drug container is unnecessary. Such compatibility evaluations are associated with considerable delay and development expenses. PCT patent application No. WO 92/01485 describes a syringe for this purpose having a glass insert and including dual pistons. The syringe, however, includes a complex barrel having multiple bores and bypass regions. This syringe requires complex molding, assembly, and sealing. However, with respect to drug administration systems, reduced cost, simplicity of design and molding, versatility of use, compatibility with automated drug dispensing systems, and ease of sterile assembly and use are the major factors defining success. It is particularly useful to provide a system using a conventional type glass vial and a convention smooth bore syringe barrel of the type in wide use and inexpensively molded of polypropylene in mass quantities and in a wide variation of bore sizes. As will be evident from the following discussion, the present invention operates to overcome many existing problems in the present art.
The sequential aspiration, mixing, and injection syringe includes a barrel having an inner wall and a main bore which is preferably conventional and smooth along substantially its entire length. The syringe includes a piston assembly having a proximal portion and a distal portion and a connecting element intermediate the portions. The portions are sized to be received into a main bore of the barrel and to fit snugly against the barrel wall. This distal portion preferably includes at least one projecting lateral member for engaging the inner walls of the barrel, thereby effectively fixing the position of the distal portion at a maximally advanced position along the barrel which preferably adjacent the distal end of the barrel, although the position could be midway along the barrel. After the pistons have been received into the barrel, the proximal portion is moveable along the barrel away from the distal portion and moveable along the barrel toward the distal portion to define a variable volume mixing chamber intermediate the proximal portion and the distal portion. The connecting element can be a fluid reservoir or a drug vial which can be comprised of glass or the connecting element can be a conduit or tube, or can be a tether or other tensile element. The glass vial can have a proximal end and a distal end. In one embodiment, both ends of the vial are open. The proximal portion can be a piston and can be positioned to occlude the proximal end and the distal portion can be a stopper to occlude the distal end of a drug vial or the distal end of a fluid reservoir or tube. The connecting element provides for mutually equivalent advancement of the proximal and distal portions along the barrel. The combined piston assembly and the connecting element can be seen to represent a reservoir or drug vial piston connectable to a syringe handle. The distal stopper is displaceable from the fluid reservoir or drug vial by retraction of the reservoir or vial away from the distal stopper and by frictional or other engagement of the distal stopper and the barrel after the reservoir or vial and the attached piston assembly have been moved to an advanced position and then the reservoir or vial is retracted from the advanced position. This allows for retraction of the proximal piston away from the distal stopper after displacement of the stopper from sealing engagement with the fluid reservoir or drug. In several embodiments, the proximal piston is further moveable along the vial toward the distal stopper. Relative advancement of the proximal piston along the vial can be caused by advancement of the handle in one embodiment wherein the proximal piston is attached to the handle. In another embodiment, wherein the proximal piston is connected to the displaced distal stopper by a tensile element, relative advancement is achieved by retraction of the vial and subsequent tensile force transmitted through the tensile element. The distal portion and the proximal portion are preferably carried by the drug vial, the distal portion being displaceable from the drug vial to open the vial into the mixing chamber, the proximal portion being moveable along the vial to displace the drug from the vial into the mixing chamber, the proximal portion effectively converting the open-ended drug vial into a closed-ended vial piston and thereafter functioning to push the drug solution within the mixing chamber out of the syringe and into a recipient with minimal deadspace-trapped drug remaining within the syringe after injection.
A method of drug injection is provided using an embodiment having a main piston or vial piston having a handle. The vial piston includes a drug vial having a proximal end and a distal end and containing stopper piston assembly having a proximal portion connected to a distal portion by a connecting element which can be a tensile element or which can be the drug vial itself, as will be described. The syringe operates, after assembly, to achieve the following drug injection method with a single retraction and advancement of the handle, steps of: 1. aspirate diluent into the main bore; 2. open the end of a drug vial into the main bore; 3. positively expel the drug from the vial; 4. subsequently convert an open-ended drug vial into a closed-ended injection piston; 5. inject the mixed drug and diluent with minimal residual drug remaining in the syringe after injection.
As noted, the present invention can utilize a drug container or vial which can be cylindrical for insertion into a syringe barrel. The drug vial is preferably made of glass or other material which can safely contain a large variety of different drugs, either in powder or liquid form. In one embodiment, the drug vial includes a closed bottom or proximal end which may include a small air vent and an open top or distal end which is preferably widely open and can, therefore, easily be filled by conventional automated drug dispensing systems. The drug vial can include a narrow neck and larger body to facilitate handling by automated equipment. The drug vial further preferably includes an outer housing member which can be polymeric. At least one sliding member is preferably provided about the vial to slidably engage the syringe barrel bore to facilitate advancement and retraction of the drug vial along the syringe barrel bore. The sliding member can be a thin rubber boot or sleeve. Alternatively, the polymeric housing member may itself be sized to sealingly engage the bore. The sliding member can be a rubber wiper of the type utilized in conventional syringe pistons or can be an o-ring or soft polymeric ring or otherwise fashioned. The sliding member is preferably carried by the housing or vial and may be positioned proximal, distal to, or along the length of the housing or vial. The outer member further can have a recess for receiving the retainer of the handle of a conventional syringe piston or, alternatively, the handle can be molded integrally with the outer vial housing member. The vial can, therefore, be connected to or contained within the handle or can be integral with a handle. In an embodiment, the vial and handle are made of glass and are integral and molded together, thereby eliminating the need for the outer polymeric housing member. In one embodiment, the vial piston includes a piston stopper assembly with a proximal stopper portion for positioning adjacent the closed end of the drug vial and a distal stopper piston portion for occluding the open end of the drug vial. Both portions can be comprised of conventional material utilized for rubber stoppers in drug vials so that contact with the drug and the rubber stopper piston assembly is provided, as is conventional, thereby eliminating the potential for material-related incompatibility. The proximal and distal portions are connected or linked by the drug vial and can be carried by the drug vial. In one embodiment, the portions are further preferably connected by a tether or by bands or other tensile connecting elements which can be comprised of conventional material used in the construction of rubber stopper pistons so as again to allow direct contact with the drug within the glass container without the need for further study to determine compatibility. The two stopper pistons can be molded as a single part with the connecting rubber tether. In one embodiment, a vent is provided for providing vent connection between the proximal face or end of the proximal piston and the atmosphere or between the proximal face of the proximal piston and the distal face or end of the distal stopper. In one preferred embodiment, the vent passes through the tether, the tether comprising a hollow tube having a bore and extending to connect bores through the proximal piston and the distal stopper. This defines a flexible tether vent which operates to limit retraction movement of the proximal piston, thereby to cause advancement of the proximal piston relative to the retracting drug vial and further to vent fluid or air into the drug vial intermediate the proximal piston and the closed end to permit advancement and to allow enlargement of an otherwise sealed nascent proximal compartment within the vial and to fill the enlarging proximal compartment with fluid. In another embodiment, the vent passes through a small opening in the otherwise closed bottom of the drug vial, the vent being occluded by the proximal piston prior to use. The vent can pass into a large volume space within a hollow handle to provide a sealed source of sterile vented atmosphere or liquid with a minimal induction of negative pressure. The width of the outer wiper may be varied so as to allow use of the same housing and vial within syringes of variable diameter and volume. This allows modification of only the wiper when different volumes of diluent are intended for use with, for example, a powdered drug so that a wide variety of variable sized vials and housings need not be constructed for syringes having bores of variable diameters.
In the manufacture of one preferred embodiment having a drug vial with a closed bottom, the proximal piston is inserted into the glass vial and this can be performed, for example, by radial compression of the proximal piston and insertion such that the proximal piston is fully advanced against the closed bottom of the glass vial. The tether or bands are preferably of adequate length to extend out through the open top of the glass vial such that the top or distal stopper does not, at this time, occlude the opening in the top of the drug vial so that powdered or liquid drug may easily be inserted at this time into the drug vial as by automated drug dispensing systems. Once an adequate volume of powdered or liquid drug has been inserted into the drug vial, the distal stopper with its associated residual tether is inserted into the top of the drug vial to occlude the opening in the drug vial. The stopper may have a laterally projecting rim and a main stopper portion which can be received by a compression fit, as is known in the art, into the glass opening to seal the opening. A distal sealing vial cover may then be provided to sealingly retain the cap and drug within the vial for long-term storage. After the vial cover has been removed, the distal stopper may be displaced from the glass opening by longitudinal force directed against the rim, away from the opening of the vial.
The distal vial stopper preferably includes flow channels. The flow channels preferably do not provide communication of the vial chamber with the atmosphere when the stopper is within the vial The flow channels can be slots along the outer laterally projecting rim or perimeter of the stopper or can otherwise be through the stopper piston. The flow channels may be defined by the inner barrel wall and the distal stopper. The channels can be longitudinally slit valves or other valves which are tightly closed at rest, but which are opened by contact with the distal end of the syringe. The laterally projecting portion of the distal stopper preferably has a diameter exceeding the diameter of the syringe bore so that the distal stopper is radially compressed by the barrel and is tightly fit within the barrel by elastic compression against the barrel wall. This allows for reliable fixation of the distal stopper within the barrel at the maximum point of advancement into the barrel, which can be adjacent the distal end of the main barrel bore. This allows the vial to be reliably and easily opened within the barrel by single handle retraction. Since the distal stopper will be fixed by tight elastic compression and frictional engagement with the wall, longitudinal retraction force on the vial will displace the vial away from the distal stopper.
In this way, each drug vial may be sized to be received into conventional automated drug dispensing equipment and can be covered and maintained for long-term storage within a conventional securely sealed polymeric enclosure. The vial can then be connected with the handle and can be packaged in a flexible sterile container along with the barrel, cannula, cannula cover, and even the diluent material in a single flexible sterile packaging enclosure for shipment and storage. The components can be completely assembled within the closed or partially closed sterile package immediately prior to use. This allows for easy packaging and storage and assures sterile assembly, which is otherwise difficult to reliably achieve when loading a piston into a syringe barrel in an open environment.
As noted, in a preferred embodiment, the handle with its vial piston is packaged with a separate syringe barrel within a single sterile flexible enclosure and constructed so that the vial piston may be unsealed and loaded into the barrel within the same sterile package which was used for storage. To prepare the vial for activation, the pharmacist can grasp a projecting tear tab on the sealing vial cover through the flexible package and remove the cover from the vial stopper, thereby exposing the enclosed distal stopper. The vial piston is then inserted into the syringe barrel by contacting the outside of the barrel through the package and inserting the distal end of the vial piston into the barrel. The vial piston is then fully advanced until the distal stopper contacts the distal end. The cannula can then be inserted into a liquid-filled compartment or container within the sterile enclosure. The vial piston can then be retracted. The syringe will then be filled by aspirating liquid enclosed within the enclosure into the barrel. The filled and mixed syringe can then be sent to the floor or to the patient's home for use, or can be frozen for long-term storage, still within the unopened and sealed original sterile enclosure.
In operation for injection, the handle is advanced until the distal stopper piston reaches a venting position along the barrel, if the handle had not previously been advanced to that position during assembly. The location of the venting position depends on the position of the source of diluent. In the preferred embodiment, the venting position is adjacent the distal end of the barrel. However, if the diluent is positioned within the syringe, the venting position can be, for example, midway along the barrel. The handle is then retracted, pulling the drug vial away from the distal stopper which includes a member or portion which is tightly retained against a portion of the barrel. This causes opening of the drug vial, thereby allowing fluid to flow into the drug vial and the drug to mix with fluid. In the preferred embodiment, the diluent fluid is stored external the syringe and the venting position is adjacent the distal end of the syringe barrel, leaving the distal stopper retained adjacent the distal end upon retraction of the vial. The distal stopper is preferably retained by tight frictional engagement with the smooth barrel or can be retained by detents along the barrel. In embodiments utilizing a tensile element, as the handle is further retracted, the tensile element will become extended, thereby transmitting tensile force to the proximal piston so that further retraction of the handle and the attached vial will cause the proximal piston to be advanced relative to the retracting drug vial so that substantially all drug and solution within the vial is pushed distally by the advancing proximal piston into the main bore or mixing chamber of the syringe. The vent preferably provides fluid communication between the vial intermediate the proximal piston and the closed vial end, thereby relieving any negative pressure within the newly enlarging closed proximal vial chamber by the passage of fluid or air through the vent into the vial proximal the proximal piston. After retraction, the solution in the mixing chamber can be agitated. If preferred, an amount of air can be initially provided during manufacture within the vial to facilitate agitation. Once the handle has been fully retracted, the proximal piston is received and retained within the distal end of the drug vial, thereby occluding the distal end of the drug vial so that the drug vial itself with its now distally occluding stopper piston now can function as a closed injection piston with the fully advanced proximal piston as its distal face. The vial can be advanced to cause injection of the mixed drug and solution into the patient with minimal residual remaining in the syringe. In one preferred embodiment, the diluent stored within the enlarging proximal chamber is later used to provide subsequent flushing of the syringe and can provide flushing of the injected drug from the deadspace of the recipient tubing. Utilizing this embodiment, during injection, once the vial piston has been fully advanced against the distal stopper, the proximal stopper is displaced from the end of the drug vial and the fluid which had been received through the vent and stored within the vial proximal the proximal piston is now displaced by the forced movement of the proximal piston back toward the closed end of the drug vial. Flow channels provided within the proximal piston allow displacement and flow of fluid from the drug vial chamber into the now virtually absent mixing chamber and out the distal conduit to flush the syringe, the conduit, and the deadspace of the tubing which is connected to the conduit and which has previously received the drug solution mixture from the conduit. This embodiment, therefore, provides for: 1) enclosed sterile insertion of a handle and piston assembly containing a powdered or liquid drug into a syringe barrel; 2) enclosed wide opening of the drug vial within the syringe barrel; 3) aspiration of diluent into free contact with the now exposed drugs from within the vial and for positive expulsion of all drug from within the vial; 4) aspiration of diluent which can later serve as a flush solution into an enlarging proximal chamber within the drug vial; 5) injection of the mixed drug solution through or around the displaced stopper into the recipient; 6) injection of the flush solution through the distal portion of the syringe and out the distal conduit to flush the syringe, the distal conduit, and at least a portion of the recipient tubing free of drug solution. It can be seen, therefore, that whether a tensile element is utilized or whether the piston handle is connected to the proximal piston, advancement of the proximal piston can be achieved for positive expulsion of the drug and, at the same time, an enlarging proximal chamber is formed within the vial which can receive fluids which can subsequently be displaced back through the distal portion of the syringe to flush the syringe.
In one embodiment, the diluent is contained within the distal portion of the syringe for mixing within the drug vial. In another embodiment, the distal conduit end of the syringe can be connected to a flexible bag containing a specific volume of diluent for aspiration into the syringe which can be stored within or can be a compartment of the main enclosing flexible package for enclosed aspiration. The conduit can be placed in fluid connection with a fluid source through a cannula connected to the distal end of the syringe. Alternatively, the fluid source may be sealingly engaged to the syringe during manufacture and then enclosed in a main flexible package. Further, alternatively, a compartment of the main flexible package containing the diluent can be sealed about the distal end of the syringe to minimize the amount of packaging required while further eliminating exposure during aspiration. A third embodiment utilizes a system wherein the syringe tip is inserted into a receiver having a one-way valve and connected to a multi-dose large volume reservoir of diluent in a hospital pharmacy of I.V. mixing area. When drug mixing is desired, the tip is inserted into the receiver and a specific volume of diluent is aspirated. The maximum aspirated volume can be preset by stops or by the length of the tether. The one-way valve prevents any potential for reflux of mixed drug solution into the reservoir.
In another preferred embodiment, the stopper assembly is provided including a connecting element intermediate the proximal piston and the distal stopper. Like the previous embodiments, the embodiment preferably includes an inner wall defining a main bore and extending to a distal tip and a conduit extending through the distal tip. The distal stopper includes projecting lateral walls for engaging. A seal is preferably provided occluding the conduit adjacent the distal tip. A diluent reservoir is further provided proximal the proximal piston and is preferably contained within the handle of the syringe. The diluent reservoir is preferably a flexible bag of fluid and is comprised of conventional material for making flexible intravenous bags of fluids, such as PVC. A flow passage way which can be a tubular extension of the PVC reservoir, is preferably provided through the proximal piston. The flow passage way is occluded by the distal stopper or can preferably be occluded by a cap which can be extracted from its occluding position along the flow passage way by the distal stopper. In the preferred embodiment, the distal stopper is integral with or is otherwise joined with the cap. The distal stopper preferably includes at least one membrane such as projecting lateral walls engaging as by tight frictional contact the inner wall or walls of the barrel, thereby effectively fixing the position of the distal stopper piston at a maximally advanced position along the barrel which is preferably adjacent the distal end of the barrel, although the position could be midway along the barrel. The flexible fluid reservoir can contain the first pharmaceutical component, which is preferably diluent or liquid drug. A second pharmaceutical component can be contained within the proximal portion of the barrel distal to the maximum advancing position of the distal stopper or can be within a drug vial connectable to a drug vial connector carried by the proximal end of the reservoir. The proximal end of the reservoir can include a reversibly sealed opening for transferring fluid from the reservoir into the drug vial and for transferring mixed drug and fluid out of the drug vial into the reservoir. In operation, the handle which has been advanced to a fully advanced position, is retracted. During retraction of the handle, the handle with its retained reservoir and proximal piston are pulled away from the distal stopper, thereby opening the distal end of the reservoir into the barrel of the syringe. Continued retraction of the handle results in negative pressure developing within the distal end of the syringe, thereby withdrawing fluid from the open end of the reservoir into the barrel. As the fluid is withdrawn, the flexible container collapses until all of the fluid is withdrawn into the barrel, at which time further retraction cannot be accomplished due to the development of a vacuum within the container. Furthermore, a detent can be provided which prevents further retraction to assure that excessive vacuum does not develop within the syringe. The flexible package dynamically collapses, thereby producing a collapsing valve mechanism preventing substantial transmission of negative pressure from the distal end of the syringe to the drug vial; although, such transmission of negative pressure would not have significant adverse consequences with the preferred embodiment in any regard. At this time, all of the mixed fluid and diluent have been displaced into a nascent mixing chamber intermediate the distal stopper and the proximal piston and subsequently this fluid can be injected by advancing the proximal piston, thereby pushing the fluid through the flow channels and the distal stopper and out the distal end of the syringe after the seal has been removed from the distal end of the syringe. A one-way valve can be provided in the flow channel through the proximal piston to prevent reflux or displacement of fluids from the mixing chamber back into the flexible reservoir during injection.
It is the purpose of the present invention to provide a drug injector which can provide long-term storage of powdered or liquid drug and subsequently allow enclosed mixing of this powdered or liquid drug with a diluent within the injector through a large opening to assure complete and easy mixing. It is the purpose of this invention to provide a distal vial stopper which can seal a reservoir or drug vial during storage, but which can provide a flow of fluid through or about the stopper once the reservoir or vial has been inserted into a syringe barrel and once the stopper has been displaced from the vial. It is further the purpose of this invention to provide a drug positioned between a piston stopper assembly connected by a tensile element within a vial so that the drug can be pushed out of the vial into a mixing area by traction on the tensile element. It is further the purpose of this invention to provide a closed drug vial which can be selectively widely opened within a closed container to allow free mixing of the drug contained within the vial with a diluent. It is further the purpose of this invention to provide a drug vial and piston stopper assembly wherein the drug vial first has a closed end containing the drug and wherein the end can be opened so that the drug can mix with a diluent and wherein the end can again be subsequently closed so that the drug vial can function as a deadspace-free piston for injecting the mixed drug solution into the patient. It is further the purpose of the invention to provide a syringe handle containing a drug vial and defining a drug vial piston within the syringe. It is further the purpose of this invention to provide a multi-compartment injection system having a syringe barrel and a piston and including a glass drug vial compartment for long-term storage of a drug, and a second compartment for storage of a specific volume of diluent and wherein the second compartment is sealed and can be positioned inside or outside the syringe so that solution may be displaced into the vial to mix with the drug by retraction of the piston along the barrel and simultaneous unsealing of the vial or the diluent compartment. It is further the purpose of this invention to provide a drug storage, mixing, and injection apparatus which allows long-term storage of a drug within a glass vial comprehensively enclosed mixture within a syringe and then complete positive expulsion of all of the contained drug into a mixing chamber within the syringe. It is further the purpose of this invention to provide a system which allows positive displacement of diluent into a syringe compartment containing powdered drug within an open-mouthed glass vial and subsequent injection of the diluent mixed with the drug utilizing closure and subsequent advancement of the glass vial within the syringe. It is further the purpose of this invention to provide a system and method for the enclosed sterile assembly of a drug mixing syringe and to provide a system for enclosed aspiration of fluid into the syringe for mixing with the drug within a single inexpensive sterile flexible enclosure. It is further the purpose of the invention to provide a syringe which can sequentially aspirate a diluent and flush solution into two separate compartments, provide for drug mixing with the diluent, and then provide sequential injection of the drug solution followed by the flush solution to flush substantially all drug from the syringe and to flush the injection site free of drug solution. For some purposes, it is preferable to provide the diluent in a manner such that the diluent is packaged within a syringe component wherein the drug vial can be packaged external to the syringe and where free and complete mixing between the drug vial and the diluent can be performed within a syringe component. In one feature of the invention, the connection of a sealing capping member of the diluent reservoir to a cap extraction member can fixedly engage a portion of the syringe barrel so that the cap can be extracted from the diluent reservoir by retraction of the diluent reservoir away from the fixed cap extraction member connected to the cap. This allows enclosed opening of a previously sealed diluent reservoir within the barrel of a syringe. In another feature of the invention, the cap extraction member includes flow channels for allowing passage of the mixed drug solution by the cap extraction member and out the syringe. In another feature of the invention, sealing occlusion of the distal tip of the syringe is provided so that negative pressure induced within the syringe withdraws fluid from a compartment proximal to the distal tip of the syringe, thereby withdrawing fluid into the syringe without the need for the fluid to be external and in fluid communication with the distal tip of the syringe. In another feature of the invention, the reservoir of fluid can carry a drug vial engaging member for connecting the drug vial to the diluent reservoir to allow free mixing between the drug vial and the diluent reservoir so that after the drug has been mixed with the diluent, the cap can be extracted by the cap extracting member and the mixed drug solution can be withdrawn into the syringe by negative pressure induced within the syringe barrel. These and other features will become evident from the summary and detailed description described below. Furthermore, these and other objects and advantages of the, invention will be further set forth in the description which follows and, in part, will be learned from the description or may be learned by practice of the invention. The objects and advantages of the invention may be realized by means of the instrumentalities and combinations particularly pointed out in the appended claims.